Anatomical, electrophysiological and neurochemical evidence suggest that the habenular (Hb) nuclei might participate in feedback control circuits involving the mesolimbic dopaminergic (DA) and serotonergic (5HT) raphe systems, which have been implicated as being involved in some psychiatric dysfunctions. The diencephalic Hb complex occupies a strategic position in the CNS, receiving diverse forebrain inputs (especially from structures comprising the limbic system) and having a discrete output to posterior nuclei. We propose to examine the nature of these transmitter interactions using selective lesions and drug treatments, combined with neurochemical assay of microdissected CNS nuclei. The effects of Hb lesions on rat DA metabolism (using radioenzymatic assay) in mesolimbic cell bodies (ventral tegmental area, VTA) or terminals (accumbens, olfactory tubercle, amygdala) and 5HT metabolism in cell bodies (dorsal raphe) or terminals (septum, hippocampus), which are parts of the limbic system, will be determined. Hb projections mediating these interactions utilize substance P (SP) and/or acetylcholine as transmitters. Therefore, SP and oxotremorine (a cholinergic agonist) will be injected systemically or directly into VTA or dorsal raphe nuclei to further characterize their influence. Neurochemical determinations made in lesioned animals will be remeasured and locomotor activity evaluated after drug treatment. These results should contribute to an understanding of the chemical substrates of the limbic system, how its components interact and what its role might be in normal CNS function.